Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an american indian population

Long, Jeffrey C.; Knowler, William C.; Hanson, Robert L.; Robin, Robert W.; Urbanek, Margrit; Moore, Elisa; Bennett, Peter H.; Goldman, David

doi:10.1002/(sici)1096-8628(19980508)81:3<216::aid-ajmg2>3.0.co;2-u

Cited by 364 publications

(300 citation statements)

References 27 publications

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“…After the complete set of 10 000 pedigrees was simulated, the F-ratio above which the most extreme ␣100% of the simulated statistics lay was the empirical ␣100% significance level. With this procedure, [37][38][39] each random pedigree maintains the genotype and phenotype correlation structure that was inherent in the original sample, but there is no relationship between the genotype and phenotype, as stipulated by the null hypothesis.…”

Section: Pedigree Randomization Analysismentioning

confidence: 99%

Early experience and serotonin transporter gene variation interact to influence primate CNS function

et al. 2002

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Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

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Section: Pedigree Randomization Analysismentioning

confidence: 99%

Early experience and serotonin transporter gene variation interact to influence primate CNS function

et al. 2002

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“…Two genome-wide scans in humans provided evidence of linkage of alcohol dependence to a region of chromosome 4p that includes a cluster of four genes encoding GABA A receptor subunits (Reich et al, 1998;Long et al, 1998). Edenberg et al (2004), by fine mapping this region, found that numerous single-nucleotide polymorphisms (SNPs) in the gene encoding the GABA A a-2 subunit (GABRA2), but not in other members of the gene cluster, were associated with alcohol dependence.…”

Section: Introductionmentioning

confidence: 99%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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GABA A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA A receptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

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“…In other investigations of interest to the current study, cigarette smoking with or without AD, were linked to broad regions of chromosomes 9 and 11. [4][5][6][7][8][9] Among the candidate addiction susceptibility genes defined by these linkage signals were those that encode the neurotrophin, brainderived neurotrophic factor (BDNF, chromosome 11), and its cognate receptor, neurotrophic tyrosine kinase receptor B (TrkB) (NTRK2, chromosome 9).…”

Section: Introductionmentioning

confidence: 99%

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

Anderson

Neyer

et al. 2007

Pharmacogenomics J

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To identify sequence variants in genes that may have roles in neuronal responses to alcohol, we resequenced the 5 0 region of tyrosine kinase B neurotrophin receptor gene (NTRK2) and determined linkage disequilibrium (LD) values, haplotype structure, and performed association analyses using 43 single nucleotide polymorphisms (SNPs) covering the entire NTRK2 region in a Finnish Caucasian sample of 229 alcohol-dependent subjects with antisocial personality disorder (ASPD) and 287 healthy controls. Individually, three SNPs were associated with alcohol dependence and alcohol abuse (AD) (P-value from 0.0019 to 0.0059, significance level was set at Pp0.01 corrected for multiple testing), whereas a common 18 locus haplotype within the largest LD block of NTRK2, a 119-kb region containing the 5 0 flanking region and exons 1-15, was marginally overrepresented in control subjects compared to AD individuals (global P ¼ 0.057). Taken together, these results support a role for the NTRK2 gene in addiction in a Caucasian population with AD and a subtype of ASPD.

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Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an american indian population

Cited by 364 publications

References 27 publications

Early experience and serotonin transporter gene variation interact to influence primate CNS function

Early experience and serotonin transporter gene variation interact to influence primate CNS function

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

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